1. Field of the Invention
The present invention relates to a novel disubstituted adamantyl derivative or a pharmaceutically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition for inhibiting cancer metastasis containing the same as an active ingredient
2. Description of the Related Art
Even after all the efforts over the past tens of years, cancer is still one of the incurable diseases. The reason why cancer is so difficult to treat is because cancer cells progress malignantly which favors the cancer cell survival and thus they invade in surrounding tissues and eventually move to other organs, that is so called metastasis. Cancer metastasis is a critical reason of death among cancer patients. Approximately ⅓ of patients diagnosed as cancer already have metastatic cancer at the time of diagnosis. Another ⅓ of cancer patients also display a minor or early stage of metastasis even though that is too early to be detected by diagnostic examinations, so that they have a great potential of having metastatic cancer when they are only treated locally for their primary cancers. That is, metastatic cancer is developed from primary cancer actually in ⅔ of cancer patients. Therefore, an efficient treating agent that can prevent and at the same time control cancer metastasis after surgical operation is urgently required.
Cancer metastasis is accomplished by the steps of adhesion, invasion, and angiogenesis. In the step of adhesion, angiopoietin-2, angiopoietin-like-4, Cox-2, MMP-1, MMP-2, MMP-3, MMP-10, PGF, and VEGF can weaken the binding between the vascular cells in the tissue where the cancer cell would want to invade in order for the cancer cells to move in easily from the blood vessel to that tissue, that is they make extravasation easy. Metastasis can be explained by the process of EMT/MET (Epithelial-Mesenchymal Transition/Mesenchymal-Epithelial Transition) which is composed of the following steps; epithelial cells are converted into mesenchymal cells and the converted mesenchymal cells migrate through blood vessels and are landed in another organ; and then the landed mesenchymal cells are converted reversely into epithelial cells. At this time, such genes as Twist, SNAIL, and ID1 induce EMT and accelerate metastasis by endowing cancer stem cell like characteristics thereto.
In the meantime, HIF-1 is the most important molecule in regulating the adaptation of cancer cell under hypoxia. Particularly, the level of HIF-1α protein is closely related to the prognosis of cancer patients. When cancer cells are under hypoxia, the cells induce HIF-1α accumultion, or the mentioned growth factors above can also induce HIF-1α activation. Also, the activation of HIF-1α can be induced by the activation of an oncogene or the inactivation of a tumor suppress gene like pVHL. The activated HIF-1α induces the expressions of hexokinase 2, glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGFA, MMP-2, MMP-9, uPAR, and MDR1, by which cancer cells acquire such characteristics as resistance against apoptosis, promoted angiogenesis, promoted cell proliferation, cell migration, metastasis, invasion, etc, resulting in the malignance of cancer.
HIF-1 also plays an important role in regulating EMT (epithelial-mesenchymal transition) related genes in the course of metastasis. HIF-1 reduces E-cadherin, but increases the expressions of fibronectin, vimentin, and Twist, suggesting that HIF-1 can promote metastasis particularly the stage of EMT. Twist not only plays an important role in gastrulation and mesoderm formation but also increases the expression of metastasis related proteins such as β-catenin and RhoA, etc, so that it has been recognized as a crucial factor for inducing EMT and cell migration (Cell Cycle, 2008, 7. 14, 2090-2096).
Up to date, studies have been actively going on to develop an anticancer agent inhibiting metastasis and also suppressing cancer stem cells by using EMT promoting transcription factors. As a result, numbers of anticancer agents such as Taxol, rapamycin, and 17-AAG (17-allylaminogeldanamycin) have been developed. These anticancer agents are to inhibit the functions of adhesion molecules including integrin family mainly expressed on the surface of cancer cells, which are exemplified by extracellular matrix components like vitronectin, laminin, and fibronectin, or to suppress MMP and type IV collagenase to inhibit metastasis (Cancer Research, 53, 2087-2091, 1993). However, the method to inhibit metastasis by using the conventional anticancer agents is only effective in inhibiting the invasion into other organs of cancer cells that have already traveled through blood stream from the organ where the cancer cells have been originally proliferated. Therefore, this conventional method is not the fundamental treatment method.
In the course of study to find out a compound that can suppress the accumulation of HIF-1α, the present inventors confirmed that the inhibition of HIF-1α resulted in the suppression of Twist expression, leading to the completion of this invention.